1. Field of the Invention
The present invention relates to a process for manufacturing 4-hydroxy-3,5-dimethoxybenzoic acid from 3,4,5-trimethoxybenzoic acid.
2. Description of the Prior Art
4-hydroxy-3,5-dimethoxybenzoic acid or syringic acid is used in the synthesis of various pharmaceutical products. It is generally obtained from 3,4,5-trimethoxybenzoic acid (TMBA) by demethylation of the 4-methoxy group. Two general methods of demethylation of phenolic ethers are known, one in an acid medium, the other in a basic medium.
In the case of TMBA, the demethylation is carried out principally in a concentrated sulphuric acid medium (G. HAHN and H. WASSMUTH, Chem. Ber. 67, 701-2, (1934))-(YOSHISHIGE KATO and MASAICHI YASUE-CA 59 11322f)-(Hungarian Pat. No. 158,280 of 24/01/69--C.A. 74 42161m). The operation is relatively long: 6 to 17 hours and necessitates considerable amounts of acid. The product obtained contains, even after recrystallization, besides a little residual TMBA, dihydroxy-monomethoxy-benzoic acid and a non-negligeable amount of an unidentified impurity. In a hydrochloric medium, under pressure, the yields from the demethylation are low; on the other hand, they are high in 48% hydrobromic acid (C. GRAEBE, E. MARTZ. Ann. Chem. 340, 220-1), but the product obtained is very impure according to the tests carried out and requires several recrystallizations.
Until now, demethylation in a basic medium has not been used to obtain syringic acid from TMBA. In fact, it was known (A. WACEK and H. KESSELRING-Monatshefte. 93. 141-150 (1962)) that TMBA was demethylated practically not at all and distinctly less rapidly than syringic acid in aqueous soda at 100.degree. C. and that, on the other hand, in aqueous or alcoholic soda, under pressure, towards 200.degree. C., the demethylation was accompanied by decarboxylation and that it was not possible to stop at the stage of syringic acid (German Pat. No. 162,658). It is known, in addition, that phenol ethers can be demethylated by heating with soda in ethylene or diethylene glycol (HOUBEN-WEYL vol. 6/3 p. 164). This same method applied to methoxyphenoxy benzoic acids causes, according to the respective positions of the carboxy and methoxy groups, either demethylation, or decarboxylation, or both at the same time (H. E. UNGNADE and L. RUBIN-J. Org. Chem. 16, 1311 and following (1951)). When the --COOH and the --OCH.sub.3 are in the para position, as in m-phenoxy, p-methoxy benzoic acid, there is demethylation and decarboxylation at the same time (H. E. UNGNADE and E. F. ORWOLL-J. Am. Chem. Soc. 65, 1736 and following (1948)). With TMBA, using the operational conditions of the literature, this method causes both demethylation and decarboxylation and leads to 2,6-dimethoxy phenol.